Candidate Therapeutics by Screening for Multitargeting Ligands: Combining the CB2 Receptor With CB1, PPARγ and 5-HT4 Receptors

In recent years, the cannabinoid type 2 receptor (CB2R) has become a major target for treating many disease conditions. The old therapeutic paradigm of one disease-one target-one drug is being transformed to complex disease-many targets-one drug. Multitargeting, therefore, attracts much attention as a promising approach. We thus focus on designing single multitargeting agents (MTAs), which have many advantages over combined therapies. Using our ligand-based approach, the Iterative Stochastic Elimination (ISE) algorithm, we produce activity models of agonists and antagonists for desired therapeutic targets and anti-targets. These models are used for sequential virtual screening and scoring large libraries of molecules in order to pick top-scored candidates for testing in vitro and in vivo. In this study, we built activity models for CB2R and other targets for combinations that could be used for several indications. Those additional targets are the cannabinoid 1 receptor (CB1R), peroxisome proliferator-activated receptor gamma (PPAR gamma), and 5-Hydroxytryptamine receptor 4 (5-HT4R). All these models have high statistical parameters and are reliable. Many more CB2R/CBIR agonists were found than combined CB2R agonists with CB1R antagonist activity (by 200 fold). CB2R agonism combined with PPAR gamma or 5-HT4R agonist activity may be used for treating Inflammatory Bowel Disease (IBD). Combining CB2R agonism with 5-HT4R generates more candidates (14,008) than combining CB2R agonism with agonists for the nuclear receptor PPAR gamma (374 candidates) from an initial set of similar to 2.1 million molecules. Improved enrichment of true vs. false positives may be achieved by requiring a better ISE score cutoff or by performing docking. Those candidates can be purchased and tested experimentally to validate their activity. Further, we performed docking to CB2R structures and found lower statistical performance of the docking (structure-based) compared to ISE modeling (ligand-based). Therefore, ISE modeling may be a better starting point for molecular discovery than docking.

Automated summary

In recent years, the cannabinoid type 2 receptor (CB2R) has emerged as a major target for treating various diseases. The development of multitargeting agents (MTAs) has gained attention as a promising approach, and ligand-based modeling has proven to be a better starting point for molecular discovery than docking. The study focuses on designing single multitargeting agents for CB2R and other targets, such as CB1R, PPAR gamma, and 5-HT4R, and explores their potential for treating Inflammatory Bowel Disease (IBD).